Project Summary/Abstract Pancreatic cancer is a devastating disease with a very low (8%) 5-year survival rate. Therapeutic options are limited in efficacy and many have substantial toxicity. Targeted drug delivery may improve the therapeutic index of cancer drugs by enhancing drug localization to the cancer cell while minimizing off-target side effects. ?2 receptors are highly expressed in pancreatic and other cancers compared to healthy cells. Accuronix Therapeutics is developing ACXT-3102, a molecule with therapeutic potential licensed from Washington University School of Medicine in St. Louis (WUSM). ACXT-3102 is comprised of a ?2 ligand covalently bound to the ferroptosis-inducing molecule erastin. Preliminary data show that ACXT-3102 increased the cytotoxicity against pancreatic tumor cells in vitro by 35-fold compared to erastin alone. ACXT-3102 has tremendous potential as a novel treatment option for pancreatic and perhaps several other types of cancer. A series of drug optimization strategies will be explored in an effort to improve the solubility, and delivery of an already viable cancer drug. The objective of these studies will be to enhance further the efficacy of ACXT-3102. For this Phase I STTR project, Accuronix Therapeutics will work with researchers from WUSM to improve the bioactivity of its lead candidate ACXT-3102. The primary endpoint is enhanced efficacy as measured by increased survival in murine models of pancreatic cancer. We will also asses for any off-target drug effects including anemia and work to minimize these by clarifying the relationship between toxicity and dose schedule. These improvement efforts will include formulation concepts commonly applied in the pharmaceutical industry to increase drug solubility in aqueous solutions ultimately leading to increases in bioavailability and, most importantly, bioactivity. The most immediate change in relation to ACXT-3102?s current composition regards the generation of seven additional salt variants. These then will be tested using alternative vehicle compositions to enhance drug half-life. Finally, the best-performing salt/formulation will be evaluated employing detailed biodistribution (PK/PD) and efficacy studies in mice via the parenteral (IV) and oral (PO) administration routes to determine the best method of delivery. At conclusion of this Phase I STTR grant, we will have demonstrated the utility of ACXT-3102 in pancreas cancer treatment, justifying advanced studies toward clinical translation for the benefit of patients suffering from pancreatic adenocarcinoma.